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ACS Comb Sci. 2015 Dec 14;17(12):722-31. doi: 10.1021/acscombsci.5b00124. Epub 2015 Dec 3.

Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor.

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Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.


DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.


DNA encoded chemical library; G-protein coupled receptor; affinity selection; cell-associated target protein; combinatorial chemistry; drug discovery

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